The entire protein devoid of large solubilising tags has been recently purified.[10] The full-length protein is a dimer.[10] The dimer is formed due to a self-interaction between two NTD domains,[6][7] where the dimerisation can be propagated to form higher-order oligomers.[6]

TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. In particular, TDP-43 is a splicing factor binding to the intron8/exon9 junction of the CFTR gene and to the intron2/exon3 region of the apoA-II gene.[11] A similar pseudogene is present on chromosome 20.[12]

TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons.[13]

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.[16] It has also shown to be a neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.[17]

Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[18] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[19]

TDP-43 protein is a key element of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNAdouble-strand breaks (DSBs) in pluripotent stem cell-derived motor neurons.[20] TDP-43 is rapidly recruited to DSBs where it acts as a scaffold for the further recruitment of the XRCC4-DNA ligase protein complex that then acts to seal the DNA breaks. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients’ spinal cord specimens there is significant DSB accumulation and reduced levels of NHEJ.[20]

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNAgenome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator "Tat" is dependent on an RNA regulatory element (TAR) located "downstream" (i.e. to-be transcribed at a later point in time) of the transcription initiation site.

Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[26] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[27][28][29] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[30] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[31] A recent study has demonstrated that cellular stress can trigger the abnormal cytoplasmic mislocalisation of TDP-43 in spinal motor neurons in vivo, providing insight into how TDP-43 pathology may develop in sporadic ALS patients.[32]